PHARMACOKINETICS: Elimination (p.1)
Concept of (plasma) “half-life”
A time measurement, which starts when the drug reaches equilibrium
(“equilibrium” = “fully absorbed” = when equal amounts of drug
are in circulation and at point of administration)
½ life = how much time it takes for blood levels of drug to decrease
to half of what it was at equilibrium
thus, there are really two kinds of ½ life…
“distribution” ½ life = when plasma levels fall to half what they
were at equilibrium due to distribution to/storage in body’s
tissue reservoirs
“elimination” ½ life = when plasma levels fall to half what they
were at equilibrium due to drug being metabolized and
eliminated
while both ½ lives contribute to the effects of the drug on
behavior, it is usually the elimination ½ life that is used to
determine dosing schedules, to decide when it is safe to put
patients on a new drug, etc.
“Rule of Five”
generally, 5x the elimination ½ life = time at which the drug is
“completely” (97%) eliminated from the body (assuming that
the drug was given in a single original dose
1x ½ life - 50% of the original drug removed
2x ½ life - 75%
3x ½ life - 87.5%
4x ½ life - 93.75%
5x ½ life - 96.875%
PHARMACOKINETICS: Elimination (p.2)
Drug metabolism/biotransformation
This mainly occurs in the liver, via liver enzymes
But it can also occur in the blood plasma or at various other places
(stomach, intestines, lungs, skin, or kidneys) directly by various
enzymes at those locations
In any case, these metabolites are then excreted/eliminated (more
easily than would the parent molecule have been)
metabolites are often smaller in size, ionized
note: some drugs are excreted/eliminated in unmetabolized form, as
the original drug molecule (e.g. Lithium)
How is drug (metabolite usually) actually excreted/eliminated?
Kidneys – in urine
Skin – in sweat
Intestines – in feces
Also in bile (in feces), saliva, breast milk,
Lungs – in exhaled breath
tears, semen, hair, nails, etc.
The Kidneys
This is the main excretory organ for drugs
Arterial blood flows past the nephron (a web of tubules & blood
Vessels)
Molecules (e.g. drug metabolites) leave arterial blood and enter the
nephron tubules
If the molecule remains in the nephron tubules, then it will be
excreted in the urine (about 2 qts. produced/day)
If the molecule gets reabsorbed back into the returning venous blood
it will be returned to general circulation (and can again have an
effect at the RS if it reaches a RS)
About 190 qts. of fluids/day are processed through the tubules,
most of which is reabsorbed
About 20% of blood plasma at any given time is being filtered
Kidneys filter > 1 liter/minute of fluids
PHARMACOKINETICS: Elimination (p.3)
How do (drug) molecules enter the tubules?
Mostly by passive filtration, flowing down their concentration
gradients, entering via pores in body capillary walls and tubule
walls (pores < 40-50 angstrom units)
How do (drug) molecules get reabsorbed into the venous blood?
Mostly by active transport (of ionized molecules)
Some by passive diffusion of non-ionized molecules (esp. if lipid
soluble)
Some by selective diffusion through specific pores (non-ionized
molecules)
note: to keep a lipid-soluble, non-ionized molecule in the tubules
(in the urine) it would be best to change it into an ionized form
which is then no-longer lipid soluble
can use “ion-trapping” here…if make urine acidic, will trap basic
molecules, if make urine basic, will trap acidic molecules
(unalikes --- ionization)
urine’s pH ranges usually from 4.5 to 7(neutral) or 8 (slightly basic)
so it usually traps bases
Other Routes of Excretion/Elimination:
In bile (which then empties into gut, excreted in feces)
1 liter/day of bile empties into duodenum
can excrete from 5 to 95% of drug dose, esp. antibiotics
water-soluble molecules get trapped in GI tract (esp. bases)…why?
lipid-soluble molecules may be reabsorbed from gut again and enter
bloodstream
In sweat, saliva, tears, exhaled breath, milk, hair, nails
Note: as heart rate increases --- pulmonary circulation --- which
then increases amounts of breath exhaled --- more drug
eliminated
Note: metabol/elim generally slower in newborns & elderly vs. adults
Note: metabol/elim in healthy children/teens may be faster than adults